Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to an agent for treating mild cognitive impairment.
• Mild cognitive impairment is also called mild memory impairment. Patients with MCI are perceived to be neither normal nor dementia, and their cognitive status is intermediate. In general, the patient has mild memory impairment, mild cognitive impairment, and minimal dysfunction in daily living functions. According to recent reports, mild cognitive impairment is associated with Alzheimer's disease because patients with MCI have a steady deterioration in dementia and their neurological status is almost always similar to Alzheimer's disease (AD). It can be considered as an early stage of the disease or a transitional state to Alzheimer's disease (Archive sub-neurology (Archi) (Archipra).
• Alzheimer's disease is a neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary tangles with neuronal degeneration.
• the senile plaque most characteristic of Alzheimer's disease is mainly composed of) 3 amyloid protein (hereinafter sometimes abbreviated as A) 3) (Biochemical Biophysical Research Communication (Biochem.
• a / 3 consisting of 40 or 42 amino acids (hereinafter abbreviated as A] 340 and 42, respectively) is known to be toxic to nerve cells (trend-in neuroscience (TINS), 16 volumes, 409 pages, (1 993), Science, 274 volumes, 99 pages (1 99
• A] 3 'drugs that inhibit secretion prevent Alzheimer's disease' Effective for treatment.
• EIA enzyme immunoassay
• This A] 3 is based on its precursor protein, APP (Amyloid Precursor
• sAPP ⁇ secreted APP
• Such neurotrophic factor-like actions include (1) the action of maintaining the survival of nerve cells, (2) the action of promoting synapse formation, (3) the action of protecting neuronal death, and (4) the long-term potentiation of the hippocampus. It recognized. Therefore, 0 secretase
• drugs that inhibit s ⁇ can be used to (1) neurodegenerative diseases, (2) cerebrovascular disorders, head trauma / spinal cord injury, sequelae of encephalitis or cerebral palsy It is also considered useful for prevention and treatment of (3) memory impairment or (4) mental illness.
• JP-A-11-80098 discloses that the formula:
• a r represents an aromatic group which may have a substituent group
• X is (i) a bond, ( ⁇ ) - S-, one SO- or a S0 2 -, (iii) Okiso and Ci _ 6 1 not a substituent selected from alkyl Le to 3 Al _ 6 may have respective Killen, C 2 6 alkenylene or C 2 - 6 Anorekiniren, (iv) -CO-O - or ( V) Formula — (CH 2 ) p— X 1 —, one (CH 2 ) pX 1 one (CH 2 ) q—,-(CH 2 ) r -CO-X 1 one, one S0 2 —NR 8 — or one (CH ⁇ ) r-SO z -NR 8 - ( wherein, X 1 is an oxygen atom or NR 8, R 8 is a hydrogen atom may be an optionally substituted hydrocarbon group or Ashiru, p is 0 An integer of 5 to 5, q
• Divalent Ci _ which may be intervened and may have a substituent 6 represents an aliphatic hydrocarbon group
• R 1 and R 2 each represent a hydrogen atom or a lower alkyl which may have a substituent, or R 1 and R 2 represent a substituent together with an adjacent nitrogen atom Forms a nitrogen-containing heterocyclic ring which may be possessed, wherein the ring A further has a substituent in addition to the group represented by the formula —X—A r (wherein each symbol has the same meaning as described above).
• JP-T-Hei 8-502587 (WO 94/10569) describes a method for identifying a] 3-amyloid-peptide (13AP) production inhibitor.
• JP-A-7-165606 describes a method for identifying a 13 AP production inhibitor.
• Japanese Patent Publication No. 10-509797 (WO 96/15452) describes a method for detecting a soluble amyloid 3 peptide in a liquid sample.
• Japanese Patent Publication No. 11-507538 discloses that a composition containing an isolated and purified enzyme that specifically cleaves an i3-amyloid precursor protein at a cleavage site of a 3-amidopeptide. Things are listed.
• JP-A-9-1178743 discloses a method for quantifying soluble APP, which comprises using an antibody against amyloid] 3 protein or soluble amyloid precursor protein (APP). Purpose of the invention
• An object of the present invention is to provide a therapeutic agent for mild cognitive impairment and to suppress progression to Alzheimer's disease.
• the present inventors have conducted intensive studies on the treatment of mild cognitive impairment, and found that a compound having an inhibitory effect on amidate protein production, secretion, aggregation and / or accumulation could be used for treatment of mild cognitive impairment and treatment of Alzheimer's disease. We found that it was effective in suppressing progress, and completed this invention.
• a prophylactic or therapeutic agent for mild cognitive impairment comprising a compound having a J3 amyloid protein production, secretion, aggregation and Z or accumulation inhibitory activity or a prodrug thereof;
• Ar represents an aromatic group which may have a substituent
• X is selected from —O—, one S—, —CO—, one SO—, -so two one and one COO— is a divalent group of was 1 or represents two which may contain divalent C _ 6 aliphatic hydrocarbon group
• Y is a divalent C 1 _ 6 aliphatic hydrocarbon group
• R 1 and R 2 are each, identical or different dates, may have a hydrogen atom or a substituent - 6 represents an alkyl, a ring a benzene ring which may have a substituent
• B ring Represents a 4- to 8-membered ring which may further have a substituent.
• the agent according to the above (1) which is a compound represented by the formula: or a salt or a hydrate thereof,
• the compound is 6_ (4-biphenylyl) methoxy-2- [2- (N, N-dimethinoleamino) ethynole] tetralin, 6- (4-biphenylinole) methoxy-12- (N, N-dimethylamino) methyl Tetralin, 6- (4-biphenylyl) methoxy-1- (N, N-dipropylamino) methyltetralin, 2- (N, N-dimethylamino) methinole 6- (4'-Methoxybiphenyl 4-) M) methoxytetralin, 6- (4-biphenylyl) methoxy 2- [2- (N, N-ethylamino) ethynole] tetralin, 2- [2- (N, N-dimethylamino) ethynole 1-6— (4,1-Methylbiphenyl-2-yl) methoxytetralin
• a compound having an activity of inhibiting amyloid protein aggregation is represented by ⁇ 1-00703,
• the agent according to the above (7) which is AL ZHEMED (NC-531), ⁇ ⁇ —368, ⁇ ⁇ —558 or S KF—74652,
• (10) a method for preventing or treating mild cognitive impairment, which comprises administering to a mammal an effective amount of a compound having an inhibitory effect on [3] amyloid protein production, secretion, aggregation and ⁇ or accumulation, or a prodrug thereof;
• FIG. 1 is a graph showing the ameliorating effect of aged rats on learning disability in Test Example 1.
• FIG. 2 is a graph showing the inhibitory effect of compound A on the accumulation of the insoluble ⁇ / 340 (FIG. 2A) and 42 (FIG. 2B) of the Swedish type ⁇ mutant transgenic mouse in Test Example 2.
• Hayashi ⁇ P ⁇ 0.01 compared to 8 months old, Student's t-tes, * P ⁇ 0.05 (compared to 13-14 month old control group, Student's t-test)
• FIG. 3 is a graph showing the inhibitory effect of compound A on the area of amyloid plaques (FIG. 3A) and the number of amyloid plaques (FIG. 3B) in a Swedish APP mutant transgenic mouse in Test Example 2. * P ⁇ 0.01 (compared to control group,
• CDR clinical dementia rating
• Examples of the compound having 0 amyloid protein production, secretion, aggregation, Z or accumulation inhibitory activity include a compound having ⁇ -secretase inhibitory activity, a compound having ⁇ -secretase inhibitory activity, and 3) a protein aggregation inhibitory activity And the like.
• Examples of the compound having a secretase inhibitory activity include a compound represented by the above formula (I) (hereinafter, referred to as compound (I)), and a salt or a prodrug thereof.
• Ar represents an aromatic group which may have a substituent.
• aromatic group of “optionally substituted aromatic group” represented by A gamma, for example, a monocyclic aromatic group, ring assembly aromatic groups, such as fused aromatic group is used
• monocyclic aromatic group for example, a monovalent group formed by removing any one hydrogen atom from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring is used.
• the “5- or 6-membered aromatic heterocycle” includes, for example, one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (for example, one to three, preferably one to two) And 5- or 6-membered aromatic heterocycles.
• concrete Examples include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, and pyridazine rings.
• monocyclic aromatic groups include phenyl, 2- or 3-phenyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2- or 4-imidazolyl, 3- Or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 2-, 4-mono or 5-oxazolyl, 2-, 3- or 4-pyridyl, 2-pyrazyl, 2-, 4- or 5-pyrimidinyl, 3 _ Or 4-pyridazinyl is used, and phenyl is preferable.
• ring-assembled aromatic group for example, two or more (preferably 2 or 3) aromatic rings are directly connected by a single bond, and the number of bonds directly connecting the rings is the number of ring systems.
• a group obtained by removing one arbitrary hydrogen atom from one less aromatic ring assembly is used.
• aromatic ring an aromatic hydrocarbon, an aromatic heterocyclic ring and the like are used.
• aromatic hydrocarbon examples include a monocyclic or condensed polycyclic (eg, bicyclic or tricyclic) aromatic hydrocarbon having 6 to 14 carbon atoms (eg, benzene, naphthalene, Inden, anthracene, etc.) are used.
• the “aromatic heterocyclic ring” includes, for example, one or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (for example, 1 to 4, preferably 1 to 2) in addition to carbon atoms.
• a to 14-membered, preferably 5- to 10-membered, aromatic heterocycle is used.
• Preferred examples of the aromatic ring assembly include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazole, isothiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
• Aromatic ring assembly consisting of two or three aromatic rings selected from 1,2,4-thiadiazole, 1,3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole and benzofuran Body and the like. More specific examples include, for example, 2-, 3- or 4-bifuyril, 3- (1-naphthyl) -1,2,4-oxadiazoyl 5-yl, 3-
• the “condensed aromatic group” includes a condensed polycyclic (preferably di- to tetra-cyclic, preferably di- or tri-cyclic) monovalent group formed by removing any one hydrogen atom from an aromatic ring. Groups are used.
• a condensed polycyclic aromatic ring a condensed polycyclic aromatic hydrocarbon, a condensed polycyclic aromatic heterocycle and the like are used.
• condensed polycyclic aromatic hydrocarbon examples include a condensed polycyclic (bi- or tricyclic) aromatic hydrocarbon having 9 to 14 carbon atoms (eg, naphthalene, indene, anthracene, etc.) Are used.
• the “fused polycyclic aromatic heterocycle” includes, for example, 9 to 14 containing one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom.
• a member, preferably a 9- or 10-membered fused polycyclic aromatic heterocycle is used.
• aromatic substances such as benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, and phthalimide A heterocyclic ring is used.
• condensed aromatic groups include, for example, 1-naphthyl, 2-naphthinole, 2-quinolinole, 3-quinoligure, 4-quinolinole, 2-benzofuraninole, 2-benzothiazolyl, 2-benzi Examples include midazolyl, 1-indolyl, 2T-indolyl, and 3-indolyl, with 1-naphthyl and 2-naphthyl being preferred.
• Examples of the substituent of the aromatic group represented by Ar include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C j-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, Shiano, optionally halogenated has good _ 6 alkyl, C 6 -. Ariruokishi -C i _ 6 alkyl (for example, such as Hue Nokishimechiru), - 6 alkyl one C 6 _! .
• a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
• C j-3 alkylenedioxy eg, methylenedioxy, ethylenedioxy, etc.
• nitro Shiano
• optionally halogenated has good _ 6 alkyl, C 6 -.
• Ariruokishi -C i _ 6 alkyl for example, such
• Aryl C 2 _ 6 alkenyl eg, methylphenyl
• optionally halogenated C 3 -6 cycloalkyl optionally substituted C 7 _ 16 aralkyl
• halogen Optionally substituted 6 alkoxy optionally halogenated 1-6 alkylthio, hydroxy, optionally substituted C 6 _! .
• aralkyloxy eg, phenylbenzyloxy
• amino, mono-C i _ 6 alkynoleamino eg, methylamino, ethylamino, propinoleamino, isopropylamino, butylamino, etc.
• aromatic group is, for example, the above substituent at a substitutable position of the aromatic group.
• each substituent may be the same or different.
• ⁇ may have a substituent
• C 7 _! As the "C 7 _ i 6 Ararukiru” 6 Ararukiru ", for example, benzyl Honoré, phenethyl, naphthylmethyl and the like.
• Nono halogenated which may be optionally _ 6 alkyl
• Nono halogenated is optionally C 3 - 6 cycloalkyl is Nono halogenated C 6 alkyloxy, C 6 alkylthio, hydroxy, amino, mono-C 6 alkylamino (e.g., methylamino, ethynoleamino, propylamino, isopropylamino, Buchiruamino etc.), di C i - 6 Arukirua amino (e.g., Jimechiruamino, Jechiruamino, Jipuropiruamino, Jibuchiruami Roh, etc.
• E Ji carbamoyl di - C i _ ⁇ Al Kill-lumbamoyl (eg, dimethylcarbamoyl, getylka / levamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated Ct- 6 alkylsulfonyl, honoleminoleamino, optionally halogenated C i ⁇ 6- anolecil-l-lupoxamide, 6- alkoxy-l-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide), _ 6- alkylsulfonylamino (eg, methylsulfonylamino) , Ethylsulfonylamino, etc.), C- 6 alkyl-carbonyloxy (eg, acetoxoxy, propanoloxy, etc.), Ci- 6 alkoxy monopropyloxy
• the “C 6 — i 4 aryl” of the “C 6 —, 4 aryl that may have a substituent” includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-indul, 2-anthryl is used. Preferred is phenyl and the like.
• C 7 — i 9 aralkyl I of “C 7 _! 9 aralkyl which may have a substituent” include, for example, benzyl, phenethyl, diphenylmethyl, triphenyl Noremethinole, 1-naphthinolemethyl, 2-naphthylmethinole, 2,2-diphene / leetinole, 3-fueninolepropinole, 4-phenylenolebutinole, 5-phenylenolepentyl, and preferably benzyl .
• Aryl carbonyl includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
• Aryl.carbonyl which may have a substituent may each have, for example, a halogen atom (eg, , Fluorine, chlorine, bromine, iodine, etc.), 3- alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C- 6 alkyl, halogenated C 3 _ 6 cycloalkyl, optionally halogenated
• Nono halogenated which may be optionally _ 6 alkylthio, hydrate port alkoxy, Amino, mono- - 6 alkylamino (e.g., Mechinoreamino, Echirua Mino, Puropiruamino, isopropyl ⁇ Mino, etc.
• Ra is (i) a hydrogen atom
• a hydrocarbon group which may have a substituent, specifically, as a substituent, a halogen atom, -3-anolexylenedioxy, nitro, cyano, or halogenated _ 6 alkyl, optionally C 3 which may be halogenated - 6 cycloalkyl Honoré, halogenated which may be Ci _ 6 Anorekokishi, optionally halogenated C - 6 alkylthio, hydroxy, Amino, mono one Ci _ 6- alkylamino, di- 6- alkylamino, optionally substituted 5- to 7-membered cyclic amino, honoleminole, carboxy, carbamoyl, optionally substituted C
• a heterocyclic group which may have a substituent, specifically, a halogen atom, C i _ 3 anolexylenedioxy, nitro, cyano, halogenated Good _ 6 alkyl, optionally halogenated C 3 _ 6 cycloalkyl, optionally nitrogenated _ 6 alkoxy, optionally halogenated
• C 1 _ 6 alkylthio, human Dorokishi, Amino, Mono one _ 6 Arukiruamino, di one C i - 6 Arukiruamino, substituents 5 which may have a 5- to 7-membered cyclic amino, Honoreminore, carboxy, force Rubamoiru, halogen may be of - 6 alkyl - carbonyl, C i _ 6 alkoxy one carbonyl, C 6 _ i Q Ari Le one carbonyl, C 6 - o Ariruokishi one carbonyl, C 7 _ 1 6 Araruki Ruokishi one carbonyl, mono one Flip ⁇ _ 6 alkyl Ichiriki Rubamoiru, di one - 6 alkyl Ichiriki Rubamoiru, C 6 _ ⁇ .
• a heterocyclic group optionally having 1 to 5 substituents selected from aryloxy,
• R aa is (i) a hydrocarbon group which may have a substituent, specifically, a halogen atom, _ 3 alkylenedioxy, nitro, cyano, or halogenated as a substituent.
• C 3 _ 6 may be also be C i one 6 alkyl, halogenated Cycloalkyl, optionally halogenated d- 6 alkoxy, optionally halogenated Ci- 6 alkylthio, hydroxy, amino, mono- 6- alkylamino, ji- 6- anolekylamino, having a substituent 5 may be 5- to 7-membered ⁇ Amino, formyl, carboxy, force Rubamoiru, halogenated which may be Rere with Ci - 6 Anorekiru Ichiriki Noreboniru, C 1 _ 6 alkoxy one carbonyl, C
• Ariru Ichiriki Rubamoiru may be halogenated _ 6 alkylsulfonyl, C 6 — D.
• Arirusu Ruhoniru, Horumiruamino, halogenated is a C one even though 6 alkyl Ichiriki Rupokisamido, C 6 - i.
• a hydrocarbon group optionally having 1 to 5 substituents, which may have 1 to 5 substituents selected from aryloxy, or
• an optionally substituted heterocyclic group specifically a halogen atom, —3 alkylenedioxy, nitro, cyano, optionally halogenated — 6 alkyl , optionally halogenated C 3 even though - 6 cycloalkyl, halogenated C i _ 6 optionally alkoxy, halogenated which may be C x _ 6 alkylthio, human Dorokishi, Amino, mono 10 _ 6- alkynoleamino, di-C, — 6- alkynoleamino, optionally substituted 5- to 7-membered cyclic amino, honoleminole, carboxy, canolebamoyl, optionally cigenated
• hydrocarbon group represented by R a and R aa a group obtained by removing one hydrogen atom from a hydrocarbon compound is used.
• a chain or cyclic hydrocarbon group eg, alkyl, alkenyl, alkynyl, Cycloalkyl, aryl, aralkyl, etc.
• chain or cyclic hydrocarbon groups having 1 to 19 carbon atoms are preferable.
• C 1 _ 6 alkyl e.g., methyl, Echiru, propyl, isopropyl, blanking chill, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, etc. to
• C 2 _ 6 Arukininore e.g., Echiniru, propargyl, 2-Bucheru, etc.
• C 3 - 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclo pentyl, cyclo hexyl, etc.
• the C 3 _ 6 cycloalkyl may be fused with one benzene ring, ! e) C 6 _ 4 Ariru (e.g., phenyl, 1 _ naphthyl, 2-Nafuchinore, 2 - indenyl, 2-anthryl), preferably phenyl,
• aralkyl eg, benzyl, phenethyl, diphenylmethyl, trifeninolemethinole, 1-naphthinolemethyl, 2-naphthinolemethinole, 2,2-diphenylenoethyl, 3-phenylenopropyl, 4-phenylenopropyl, 5-phenylphenol Dinorpentyl
• benzyl e.g, benzyl, phenethyl, diphenylmethyl, trifeninolemethinole, 1-naphthinolemethyl, 2-naphthinolemethinole, 2,2-diphenylenoethyl, 3-phenylenopropyl, 4-phenylenopropyl, 5-phenylphenol Dinorpentyl
• the heterocyclic group represented by R 3 and R aa includes, for example, one or two, preferably 1 to 4 (preferably 1 to 3) selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing a heteroatom, preferably (i) 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, (ii A 5- to 10-membered non-aromatic heterocycle or (iii) a monovalent group formed by removing any one hydrogen atom from a 7- to 10-membered bridged heterocyclic ring is used.
• Examples of the “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic ring” include, for example, thiophene, benzothiophene, benzofuran, benzimidazonole, benzoxazole, benzothiazole, benzisothiazonole, Naft
• 5- to 10-membered non-aromatic heterocycle for example, pyrrolidine, imidazoline, virazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine and the like are used.
• 7- to 10-membered bridged heterocyclic ring for example, quinutalizine, 7-azabicyclo [2.2.1] heptane and the like are used.
• heterocyclic group is preferably a 5- to 10-membered (1- or 2-membered (including 1 or 2 and preferably 1 to 4 heteroatoms) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
• Monocyclic or bicyclic) heterocyclic group is preferably a 5- to 10-membered (1- or 2-membered (including 1 or 2 and preferably 1 to 4 heteroatoms) selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
• Aromatic heterocyclic groups such as soquinolyl, pyrajunole, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolinole, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolinole, 2-indolyl, and 2-isoindolinyl
• a 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms is preferable.
• C _ 6 alkyl represented by R b, for example, methyl, Echiru, flop Ropinore, isopropyl, heptyl, isobutyl, sec Buchinore, tert Buchi Le, pentyl, Kishinore the like.
• the "nitrogen-containing heterocycle" formed by Ra and Rb together with an adjacent nitrogen atom is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom containing at least one nitrogen atom in addition to a carbon atom
• a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 hetero atoms is used, and examples thereof include piperidine, morpholine, thiomorpholine, piperazine, and pyrrolidine.
• Preferable examples of "acyl J" as a "substituent" of the "aromatic group” represented by Ar include formyl, carboxy, carbamoyl, and optionally non-fluorinated C
• C 1 - 6 alkoxy - carbonyl e.g., methoxy Kanoreboninore, ethoxy Kano repo - Honoré, propoxy Kano levo Nino les, tert such as single-butoxy Kanoreponiru
• C 6 1 J 0 aryl-carbonyl optionally substituted C 6 —, 0 aryloxy monocarbonyl, optionally substituted C 7 — x 6 arylalkyloxy monocarbonyl, optionally substituted 5- to 6-membered heterocyclic carbonyl, mono-C- 6 alkyl-carbamoyl, di-
• heterocyclic force members 5-6 may have a substituent group
• Luba moil may be halogenated - 6 alkylsulfonyl, optionally have a substituent C 6 - 10 arylsulfonyl and the like.
• C 7 _ i 6 Ararukiruokishi one carbonyl of the "substituents optionally C 7 _ J 6 Ararukiruokishi one carbonyl optionally having", for example, benzyl O alkoxycarbonyl, such as Hue phenethyl Ruo alkoxycarbonyl is used.
• Examples of the “5- to 6-membered heterocyclic carbonyl j” of the “5- to 6-membered heterocyclic carbonyl optionally having substituent (s)” include, for example, nicotinoyl, isonicotinoyl, 2-tenoinole, 3-tenoinole, 2-floinole, 3 -.
• Furoinore, mono Reho Reno Kano levo sulfonyl, Piperijinokarubo two Honoré, and 1-pyrrolidin Rukaruponiru is used "optionally substituted C 6 -. i Ari Le Ichiriki Rubamoiru".
• Examples of “one-strength rubamoyl” include phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoinole, and the like.
• the "5- to 6-membered heterocyclic canolebamoyl J optionally having substituent (s)" as the “5- to 6-membered heterocyclic carbamoyl” includes, for example, 2-pyridylcarbamoy Nore, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-Chenolecalcarbamoyl, 3-Chenylcarbamoyl and the like are used.
• C 6 of the” optionally substituted C 6 _ 0 ⁇ reel sulfonyl! "-.
• I is the ⁇ reel sulfonyl j, for example, benzenesulfonyl, 1 one naphthalenesulfonyl, 2-naphthalate Rensuruhoniru Are used.
• C 6 — 1 which may have a substituent.
• Aryl-carbonyl “C 6- ! 0 aryloxy-carbonyl which may have a substituent”, “also a good C 7 -! 6
• Ararukiruokishi - carbonyl optionally substituted heterocyclic carbonyl may also be 5- to 6-membered have a ",” optionally substituted C 6 _ j Ariru -. power Rubamoiru , "A 5- or 6-membered heterocyclic group optionally having substituents, norevamoyl” and "C 6 _, optionally having substituent (s).
• acylamino as the “substituent” of the “aromatic group which may have a substituent” represented by Ar above includes, for example, “an aryl group having a substituent represented by Ar” Amino or the like substituted with one or two amino acids by the ⁇ acyl '' described in the ⁇ substituent group '' of the ⁇ aromatic group '' may be used.
• Rc is a hydrogen atom or a Ci - 6 alkyl
• R da is as defined above R aa
• Ci As “Ashiruamino" as the "substituent" of the "optionally substituted aromatic group” represented by A r, preferably, Horumiruamino, Nono halogenated by _ 6 may Ci also be alkyl one Karubokisami And C 6 _ 1 which may have a substituent.
• Ariru - Karubokisami de eg, phenylalanine carboxamide, etc. Nafuchirukaruboki Samido
• C _ 6 Anorekokishi one carboxamide (example, main Tokishikarubokisa Mi de, ethoxycarboxamido Mi de, propoxy carboxamide, etc.
• Butokishikaruboki Samido - 6 alkylsulfonyl ⁇ Mino (eg, methylsulfonylamino, ethylsulfonylamino, etc.) and the like are used.
• acyloxy as the “substituent” of the “aromatic group which may have a substituent” represented by Ar above, for example, the above-mentioned “optionally substituted” such Okishi which is substituted "Ashiru” with one detailed in the “substituent” of the stomach aromatic group "is used, preferably, the formula: a O-COR e, one O-COOR e or a 0-CONHR e
• R e is as defined above R a] such Ashiruokishi represented by is found using.
• Ci - 6 alkyl one carbonyl O carboxymethyl eg, Asetokishi, prop noisy Ruo carboxymethyl etc.
• Ci - 6 alkyl one carbonyl O carboxymethyl eg, Asetokishi, prop noisy Ruo carboxymethyl etc.
• C 6 - 1 0 Ariru one Kano levo Nino Les oxy e.g., Benzoiruokishi, 1 Nafutoi / Leo carboxymethyl, 2-Nafutoiruokishi
• - 6 alkoxy one carbonyl O carboxymethyl
• Allyl-carbamoyloxy eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.
• nicotinyloxy etc.
• C 6 —x e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.
• Aryl-carboxamide e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.
• nicotinyloxy etc.
• biphenyls such as 2-, 3- or 4-biphenylyl are preferred.
• X may contain one or two divalent groups selected from one O—, one S—, one CO—, one SO—, —so 2 and —COO— 2 valent - 6 aliphatic hydrocarbon group
• Y represents a divalent _ 6 aliphatic hydrocarbon group.
• Ji 1 _ 6 aliphatic hydrocarbon group C _ 6 alkylene, C 2 _ 6 Aruke two alkylene, C 2 _ 6 alkynylene are used.
• the 6 alkylene for example, one CH 2 - - the ⁇ 1, - (CH 2) 2 -, one (CH 2) 3 -, one (CH 2) 4 -, i (CH 2) 5 - one (
• a linear Ci- 6 alkylene such as CH 2 ) 6 —, and optionally having 1 to 3 C-3 alkyls
• _ 3 azolexylene eg, one CH 2 —, one (CH 2 ) 2 —, One (CH 2 ) 3 —, etc.
• the C 2 - The 6 alkynylene for example, one C ® C-, one CH 2 - C ⁇ C-, -C ⁇ C-CH 2 -, one C ⁇ C one CH 2 CH 2 one, -CH 2 CH 2 - C [identical to] C one, -CH 2 -C ⁇ C-CH 2 - , one a (CH.) - C ⁇ C- CH 2 one one (CH 2) 2 -C ⁇ C- (CH 2 ) 2 —, 1 (CH 2 ) 3 — C ⁇ C-1 CH 2 — and other linear C 2 — 6 alkynylene, as well as 1 to 3 _ 3 alkyls the optionally Rere include C 2 - 3 alkynylene (e.g., one C ⁇ C one, one CH 2 - C ⁇ C- one C ⁇ C-CH 2 -, -C ⁇ C- CH 2 CH 2 one , -CH 2 CH 2 — C ⁇ C— etc.) are used.
• ⁇ 1 _ 6 aliphatic hydrocarbon group in particular, C t _ 3 alkylene, C 2 - 3 alkenylene, C, such as C 2 _ 6 alkynylene - like 3 aliphatic hydrocarbon group virtuous preferable.
• X is preferably —O— containing one —O-3 phenol
• Y is preferably alkylene of Ci — 3.
• R 1 and R 2 in the compounds (I) are each the same or different, represents an Ci _ 6 alkyl optionally having substituent a substituent.
• R 1 and R 2 definitive "optionally substituted Ci - 6 alkyl" - as "C 1 6 alkyl” includes, for example, Mechinore, Echiru, propyl, isopropyl, Puchinore, Isopuchinore, sec- Buchinore, Tert-butynole, pentynole, hexinole and the like are used, and among them, methyl, ethyl, propyl and the like are preferable.
• a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
• Ci— 3 alkylene O carboxymethyl eg, Mechirenjiokishi, etc.
• Echirenjioki sheet two collected by filtration, Shiano, halogenated which may be C _ 6 alkyl, Nono halogenated which may be C 3 - 6 cycloalkyl lambda ⁇ , halogen of which may have been not good Ci _ 6 Anorekokishi, halogenated which may be C i: - 6 alkylthio, human Dorokishi, amino, mono one Ci - 6 alkylamino (e.g., Mechinoreamino, Echinore amino, Puropiruamino, isopropyl ⁇ Mino, etc.
• Ci - 6 alkylamino e.g., Mechinoreamino, Echinore amino, Puropiruamino, isopropyl ⁇ Mino, etc.
• Anoreki Rucanolebamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C i- 6 alkyl-only rubamoinole (eg, dimethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, etc.), may be halogenated _
• 6 alkylsulfonyl, Horuminoreamino, Nono halogenated which may also be C i _ 6 alkyl one Karubokisami de, Ji _ 6 alkoxy one Karubokisami de (e.g., main Toki Shikarubokisami de, ethoxycarboxamido Mi de, propoxy carboxamide Mi de, butoxy carboxamide, etc.), - 6 alkylsulfonyl ⁇ amino (e.g., methylstyrene Ruhoniruamino, E chill sulfonyl ⁇ amino etc.), - 6 alkyl one carbonylation Ruokishi (eg, Asetokishi, prop Noi Ruo carboxymethyl, etc.), - 6 Anorekokishi one Kanoreponiru Oxy (eg, methoxy canoleponinoleoxy, ethoxycarbonyl / reoxy, propoxycarbonyloxy, butoxycanolepon
• 6- alkyl-lumbamoyloxy eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.
• di- 6- alkyl-lumbamoyloxy eg, dimethylcarbamoyloxy, getylcarbamoyloxy, etc.
• substituents preferably one to three good aromatic groups are used. When the number of substituents is two or more, each substituent may be the same or different.
• Ring A in compound (I) represents a benzene ring which may further have a substituent. That is, the ring A may further have a substituent at a substitutable position in addition to the group represented by the formula Ar—X—.
• substituents for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), halogenated which may be C 1 _ 6 alkyl, ⁇ Ji may be halogenated - 6 Alkoxy, hydroxy, amino and the like are used.
• halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
• halogenated which may be C 1 _ 6 alkyl
• ⁇ Ji may be halogenated - 6 Alkoxy, hydroxy, amino and the like are used.
• substituent of the ring A in particular, a halogen atom (e.g., chlorine, etc.), C x _ 6 Anorekokishi (e.g., methoxy, etc.) and the like are preferable.
• Ring A is represented by the formula A r— X— It is particularly preferred that the compound is substituted only with a group represented by
• Ring B in compound (I) represents a 4- to 8-membered ring which may further have a substituent.
• the 4- to 8-membered ring represented by ring B may contain one double bond other than the portion fused to ring A, and is selected from an oxygen atom, a nitrogen atom and a sulfur atom other than a carbon atom.
• 4- to 8-membered homo- or heterocyclic rings which may contain 1 to 3 heteroatoms.
• Z is (i) a bond, (ii) C x _ 4 alkylene or (iii) C 2 - include the rings represented by showing a 4 alkenylene].
• Z is preferably —3 alkylene, more preferably ethylene.
• the “4- to 8-membered ring” is preferably a compound represented by the formula:
• Z is as defined above].
• it is a 6-membered homo- or heterocyclic ring which does not contain a double bond except at the portion fused to the ring A and may contain one oxygen atom or imino other than a carbon atom. is there.
• substituent of the “optionally substituted 4- to 8-membered ring” represented by ring B, for example, oxo, — 6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) Etc.), hydroxy and the like.
• the substituent may be substituted with 1 to 3 substituents at substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different.
• Ring B is preferably of the formula:
• C is represented by 6-membered homocyclic or heterocyclic ring having no substituent in addition to group in
• the fused ring formed by ring A and ring B preferably has the formula:
• Compound (I) can be produced according to the production method described in JP-A-11-80098 (W098 / 38156) or WO01 / 74756.
• Examples of the compound having y-secretase inhibitory activity that can be used include, for example, a compound represented by the formula:
• Compounds having an activity of inhibiting protein aggregation include PT I-0 703, AL ZHEMED (NC-531), and the formula:
• Salts of compounds having an inhibitory effect on amyloid protein production, secretion, aggregation and Z or accumulation include, for example, salts with non-m3 ⁇ 4 groups, ammonium salts, salts with existing TO groups, salts with inorganic acids, and organic acids. And salts with basic or acidic amino acids.
• the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; and an aluminum salt.
• the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolanolamine, dicyclohexanolamine, ⁇ , ⁇ -dibenzylethylenediamine. Salts with amines are used.
• Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
• Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, A salt with ⁇ -toluenesulfonic acid or the like is used.
• Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
• Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salt is used.
• salts pharmaceutically acceptable salts are preferred.
• an alkali metal salt for example, sodium salt, potassium salt, etc.
• alkaline earth Metal salts e.g., canoledium salt, magnesium salt, barium , Ammonium salts and the like, and when these compounds have a basic functional group, hydrochloride, sulfate, phosphate, hydrobromide And inorganic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, P-toluenesulfonate, citrate, and tartrate.
• salts such as hydrochloride, citrate and fumanoleate are particularly preferred.
• the compound having an inhibitory effect on J3 amyloid protein production, secretion, aggregation and / or accumulation may be any of an anhydride and a hydrate. In the case of a hydrate, it may have one to three H 2 O molecules.
• compound (I) may produce a stereoisomer depending on the type of the substituent. May be used alone or as a mixture thereof.
• the compound (I) in the case where the compound (I) exists as a force configurational isomer (configuration isomer), diastereomer, conformer, or the like, it may be isolated by a known separation and purification means, if desired. Can be. Further, when the compound (I) is in a racemic form, it can be separated into d-form and 1-form by ordinary optical resolution means. In the present invention, these separated isomers may be used or may be used as a mixture. In particular, it is often preferable to use an optically active substance.
• a compound having an inhibitory effect on amyloid protein production, secretion, aggregation and / or accumulation may be a prodrug thereof.
• the prodrug is a compound which is converted into a compound having an inhibitory action on i3 amyloid protein production, secretion, aggregation and Z or accumulation by a reaction with an enzyme or stomach acid under physiological conditions in a living body.
• a compound that undergoes reduction, hydrolysis, etc., and changes to these compounds and (2) A compound, which undergoes hydrolysis, etc., due to stomach acid, etc., to change to these compounds.
• prodrugs of compounds having amyloid protein production, secretion, aggregation, Z or accumulation inhibitory activity compounds having a hydroxyl group of these compounds which are acylated, alkynolelated, phosphorylated, borated, or salts thereof (for example, the hydroxyl groups of these compounds are converted to acetyl, noretoyl, propanoyl, vivaloyl, succinyl, Fumarylation, alanylation, dimethylaminomethylcarbonylated compound or a salt thereof), or a compound in which the carboxyl group of these compounds is esterified or amidated (for example, the carboxyl group of these compounds is Ethyl esterification, phenyl esterification, canolepoxoxymethyl esterification, dimethylaminomethinole esterification, pivaloneoleoxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
• 3-amyloid protein production, secretion, compounds having aggregation and Z or accumulation inhibitory effect isotope is labeled with a May be.
• the above-mentioned compound (including salt) or prodrug (hereinafter simply referred to as a 0-amyloid protein inhibitory compound) having an inhibitory action on amyloid protein production, secretion, aggregation and Z or accumulation is, It is useful for the treatment of mild cognitive impairment due to its secretion, aggregation and Z or accumulation inhibitory effects.
• Amyloid protein inhibitory compounds are used in the treatment of mild cognitive impairment, such as drugs for treating Alzheimer's disease (for example, cholinesterase inhibitors such as donezil, rivastigmine, galantamine, TAK-147, etc., idebenone, memantine, vinpocetchi Cerebral function enhancers), antiparkinsonian drugs (eg, L-dopa, deprenyl, urenovidopa + levodopa, penoregolide, robinironole, power benoregorin, pramidixole, entacablon, lazabemide, etc.), muscle atrophy Drugs for lateral spinal cord sclerosis (eg, riluzole, mecamermin, gabapentin, etc.), neurotrophic factors, antidepressants (eg, fluoxetine, sertraline, paroxetine, venlafaxine, Fazodone, repoxetine, imipramine hydro
• amyloid protein-inhibiting compound used in the present invention in particular, compound (I), can be used in combination with the above-mentioned medicine to produce not only mild cognitive impairment but also neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease) Disease, Kreutzfeldt-Jakob disease, amyotrophic lateral cord sclerosis, diabetic neuropathy, etc., cerebrovascular disorder (eg, cerebral infarction, cerebral hemorrhage, cerebral circulation failure due to cerebral arteriosclerosis, etc.), head injury -Neurological dysfunction, memory disorders (eg, senile dementia, amnesia, etc.) or mental disorders (eg, depression, panic disorder, schizophrenia, etc.) at the time of spinal cord injury, encephalitis sequelae or cerebral palsy It can be used effectively for prevention and treatment.
• a j3 amyloid protein inhibitory compound, particularly compound (I), a salt thereof or a prodrug thereof has low toxicity and has excellent trans
• these compounds can be safely used as therapeutic agents for mild cognitive impairment in mammals (eg, rats, mice, guinea pigs, egrets, hidges, pomas, stags, pests, monkeys, humans, etc.). It is.
• the therapeutic agent for mild cognitive impairment of the present invention can be produced by formulating the above-mentioned ⁇ -amyloid protein inhibitory compound according to a method known per se.] 3 Amyloid protein inhibitory compound A compound as it is or a pharmacologically acceptable carrier
• Pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, It can be a sustained-release preparation and can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.).
• the content of the 0-amyloid protein inhibitory compound in the therapeutic agent for mild cognitive impairment of the present invention can be appropriately selected according to the efficacy of each compound.
• the content of compound (I) is Usually about 0.1 to 100 weight. /. It is.
• the dosage varies depending on the administration subject, administration route, disease, etc.
• active ingredient Compound (I) About 0.01 to 500 mg, preferably about 0.1 to 100 mg, more preferably ⁇ to 100 mg, and can be administered in 11 to several divided doses .
• Examples of the pharmacologically acceptable carrier used in the production of the therapeutic agent for treating mild or intellectual impairment of the present invention include various organic or inorganic carrier substances commonly used as a drug substance. Excipients, lubricants, binders, disintegrants; solvents in liquid preparations, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
• excipient for example, lactose, sucrose, D-mannitol, starch, corn starch (corn starch), crystalline cellulose, light caffeic anhydride and the like are used.
• lubricant examples include magnesium stearate and calcium stearate.
• Talc, colloidal silica, etc. are used.
• binder for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropinoresenololose, hydroxypropinolemethinoresenorelose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, Carboxymethylcellulose sodium is used.
• disintegrant for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarnomelose sodium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like are used.
• solvent for example, water for injection, alcohol, propylene glycol, Mackerel gall, sesame oil, corn oil and the like are used.
• melting angle auxiliary examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
• suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol And hydrophilic polymers such as polyvinylinolepyrrolidone, sodium carboxymethinolecellulose, methinoresenorelose, hydroxymethinoresenorelose, hydroxyxetinorescellulose, and hydroxypropylcellulose.
• surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
• polyvinyl alcohol And hydrophilic polymers such as polyvinylinolepyrrolidone, sodium carboxymethinolecellulose, methinoresen
• buffers such as phosphate, acetate, carbonate, and citrate are used.
• the soothing agent for example, benzyl alcohol and the like are used.
• preservative for example, paraoxybenzoic acid esters, chlorobutanoic acid, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are used.
• Antioxidants include, for example, sulfites, asconolevic acid, and sodium ascorbate Lium or the like is used.
• the preparation may be provided with a light-shielding coating according to a conventional method for stabilization to light or the like.
• a light-shielding coating base hydroxypropyl methyl cellulose, ethyl cellulose / rose, hydroxymethyl cellulose and the like can be used. Titanium oxide, iron sesquioxide and the like may be added to these bases.
• polyethylene glycol or the like may be added as a plasticizer for the film.
• copolyvidone can be suitably used as the plasticizer.
• (+) — N, N-dimethyl-1- (6- (4-biphenylyl) methoxy-2-tetratraline) acetamide (Obtained according to the method described in JP-A-11-310561) 695 g in 3475 mL of toluene Under a nitrogen stream, 562 g of sodium dihydro-bis (2-methoxyethoxy) aluminate (70% toluene solution) was added dropwise at an internal temperature of 20 ° C or less. After stirring at room temperature for 1.5 hours, 695 mL of aqueous 41 ⁇ sodium hydroxide solution was added dropwise at 20 ° C or lower, and the mixture was stirred at room temperature for 30 minutes and then separated.
• the organic layer was washed twice with 695 mL of a 1N aqueous sodium hydroxide solution and twice with 139 OmL of water.
• 348 mL of toluene was added to the organic layer, and the mixture was heated to 60 ° C, and 175 mL of concentrated hydrochloric acid (content: 36%) was added dropwise.
• the precipitated crystals were collected by filtration, and washed with 695 mL of Tonolen and 139 OmL of a 50% aqueous methanol solution. After drying under reduced pressure at 40 ° C, the title compound was obtained as pale yellow crystals (723 g, yield: 94.
• Tetraline hydrochloride monohydrate (479.8 g) was dissolved in a mixture of tetrahydrofuran (3186 mL) and water (864 mL) at 60 ° C. 24 g of activated carbon was added and the mixture was stirred at 60 ° C for 30 minutes. The activated carbon was removed by filtration and washed with a mixture of 336 mL of tetrahydrofuran and 216 mL of water. The filtrate was heated to 60 and 2688 mL of tetrahydrofuran was added dropwise with stirring.
• the therapeutic agent for mild cognitive impairment of the present invention was produced.
• the condyles were compressed to a weight of 15 Omg with a tableting machine using a 7.5 mm diameter punch to give uncoated tablets.
• the obtained uncoated tablets are sprayed with a solution of hydroxypropylmethylcellulose 2910 in which titanium oxide and iron sesquioxide are dispersed and copolyvidone in a film coating machine, and 1.15 mg of compound A per tablet shown in Table 1. About 1500 tablet tablets were obtained. Similarly, 5 mg tablets and 5 Omg tablets were produced.
• Fisher344 rats male, 27 months old, male were preliminarily subjected to four trials of a water maze task (pool with a diameter of 9 Ocm) with the platform on the water. Rats showing significant impairment in swimming ability were excluded and grouped. Thereafter, Compound A (0.3 or 1.0 mg / kg, oral) was administered once 1 ⁇ for 14 days. On the 10th, four trials of the water maze task with the platform on the water confirmed that there was no problem with swimming ability. From the next day, the water maze test was performed 4 times a day for 3 days. In this test, a 120 cmS: diameter pool was used to measure the time required to reach a platform submerged under water. Two trials were represented as one block. During the behavioral pharmacology study, the drug was administered after the study was completed.
• Swedish amyloid precursor protein ( ⁇ ) mutant transgenic mice (7-8 months old) were fed a solid diet (56 ppm) or control diet containing compound ⁇ (equivalent to about 7 mg Zkg gZ) for 6 months.
• the cerebral hemisphere was used for brain histological examination, and the remaining hemisphere was used for measurement of A340 / 42 content.
• the cerebral cortex was used for the measurement.
• Accumulation of insoluble A] 340Z42 protein was first homogenized with a 25-fold amount of Tris buffer (containing a protease inhibitor), and the centrifuged supernatant was removed. Thereafter, a 19-fold amount of 70% formic acid was added to the insoluble precipitate, homogenized and solubilized.
• the amount of A] 340-42 contained in the centrifuged supernatant was diluted 20-fold with a 1 M Tris solution, neutralized, and then subjected to quantification. Accumulated A] 340Z42 was quantified by enzyme immunoassay.
• mice For histopathological examination, two sections including the dorsal hippocampus were prepared for each mouse, and A340 / 42 was immunostained with BAN50 to measure the number of amyloid plaques and the area of amide plaques .
• the vehicle (control) group used 13 cases, and the compound A administration group used 16 cases.
• Figure 2 shows the amounts of insoluble A] 340 and 42 when the vehicle or compound was administered for 6 months.
• the amount of A] 340 at 13-14 months of age in the Swedish APP mutant transgenic mouse was increased about 35-fold compared to 8 months of age.
• a ⁇ 42 content increased about 25-fold.
• the amount of A] 340 and A] 342 was significantly reduced by about 30% in the compound II administration group. During the dosing period, the mice did not lose weight and had no effect on the general symptoms of the animals.
• Figure 3 shows the number and area of amyloid plaques.
• Compound A administration is amyloid
• the number and area of plaques were significantly reduced, to 40 and 35% of the control group, respectively.
• amiloid plaque formation is already in progress, and a compound A, which is presumed to enter Alzheimer's disease when a certain threshold is exceeded, inhibits] 3 secretase and produces, secretes, aggregates and azoids amyloid. It was found to inhibit accumulation.
• an effective therapeutic agent for mild memory impairment can be provided, and transition to Alzheimer's disease can be suppressed.

Landscapes

• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

Family

ID=19188846

Family Applications (1)

Country Status (6)

Cited By (2)

Families Citing this family (6)

Citations (2)

Family Cites Families (7)

• 2002
  • 2002-12-25 WO PCT/JP2002/013478 patent/WO2003055521A1/ja not_active Application Discontinuation
  • 2002-12-25 US US10/499,354 patent/US20050085553A1/en not_active Abandoned
  • 2002-12-25 AU AU2002367106A patent/AU2002367106A1/en not_active Abandoned
  • 2002-12-25 EP EP02790853A patent/EP1459764A4/de not_active Withdrawn
  • 2002-12-25 CA CA002471531A patent/CA2471531A1/en not_active Abandoned
  • 2002-12-25 JP JP2002374586A patent/JP4354180B2/ja not_active Expired - Fee Related

Patent Citations (2)

Non-Patent Citations (10)

Also Published As

Similar Documents

Legal Events